Background-Peripheral chemoreceptor hypersensitivity is a feature of abnormal cardiorespiratory reflex control in chronic heart failure (CHF) and may contribute to sympathetic overactivity, attenuated baroreflex sensitivity (BRS), and excessive ventilation during exercise. We studied whether augmented peripheral chemosensitivity carries independent prognostic significance. ) predicted impaired survival (hazard ratio 3.2, 95% CI 1.6 to 6.0, Pϭ0.0006). In the 27 patients (34%) with high peripheral chemosensitivity, 3-year survival was 41% (95% CI 22% to 60%) compared with 77% (66% to 89%) in 53 patients with normal chemosensitivity (Pϭ0.0002). In multivariate analyses, augmented chemosensitivity independently predicted death (hazard ratio 2.8, 95% CI 1.5 to 5.5, adjusted for age, peak V O 2 , and V E/V CO 2 [Pϭ0.002]; hazard ratio 2.6, 95% CI 1.3 to 5.1, adjusted for age, LVEF, and peak V O 2 [Pϭ0.008]). Depressed BRS was related to unfavorable prognosis in univariate analysis (Pϭ0.05) but not in multivariate analyses. Conclusions-Hypersensitivity of the peripheral chemoreceptors independently predicts adverse prognosis in ambulatory patients with CHF. This hyperactive excitatory reflex, through its inhibitory effect on the baroreflex, may be the reason for the previously observed prognostic association of the latter.

Background-Oscillatory breathing patterns characterized by rises and falls in ventilation with apnea (Cheyne-Stokes respiration [CSR]) or without apnea (periodic breathing [PB]) commonly occur during the daytime in chronic heart failure (CHF). We have prospectively characterized patients with cyclical breathing in terms of clinical characteristics, indices of autonomic control, prognosis, and the role of peripheral chemosensitivity. Methods and Results-To determine cyclical breathing pattern, power spectral analysis was applied to 30-minute recordings of respiration in 74 stable CHF patients. Analyses of heart rate variability and baroreflex sensitivity were used to assess autonomic balance. Peripheral chemosensitivity was assessed with the transient hypoxia method. We also determined whether the suppression of peripheral chemoreceptor activity (hyperoxia or dihydrocodeine) would influence the respiratory pattern. Cyclical respiration was found in 49 (66%) patients (22 [30%] CSR, 27 [36%] PB) and was associated with more advanced CHF symptoms, impaired autonomic balance, and increased chemosensitivity (0.80 and 0.75 versus 0.34 L ⅐ min Ϫ1 ⅐ %SaO 2 Ϫ1 , PϽ0.001, for CSR and PB versus normal breathing, respectively). Transient hyperoxia abolished oscillatory breathing in 7 of 8 patients. Dihydrocodeine administration decreased chemosensitivity by 42% (Pϭ0.05), which correlated with improvement in respiratory pattern. Cyclical breathing predicted poor 2-year survival (relative risk 9.41, PϽ0.01, by Cox proportional hazards analysis), independent of peak oxygen consumption (Pϭ0.04). Conclusions-An oscillatory breathing pattern during the daytime is a marker of impaired autonomic regulation and poor outcome. Augmented activity of peripheral chemoreceptors may be involved in the genesis of this respiratory pattern. Modulation of peripheral chemosensitivity can reduce or abolish abnormal respiratory patterns and may be an option in the management of CHF patients with oscillatory breathing. (Circulation. 1999;100:2418-2424.)

Skeletal muscle function was measured as force production and fatigue in both the quadriceps (a large locomotive muscle) and adductor pollicis (a small intrinsic hand muscle) in five healthy volunteers, five patients with mild chronic heart failure, and five patients with severe chronic heart failure. The quadriceps of patients with chronic heart failure had a reduced muscle cross sectional area, a reduced maximum isometric force production, and an increased tendency to fatigue. Isometric force production and fatigue of the adductor pollicis, however, were not significantly different between the three groups under control conditions. But during circulatory occlusion fatigue in the adductor pollicis increased more in the patients with severe chronic heart failure. These differing findings in quadriceps and adductor pollicis suggest that skeletal muscle atrophy and reduced isometric force production are not a necessary consequence of chronic heart failure per se, because they were only present in the large locomotive muscle. The normal values for muscle fatigue observed in adductor pollicis in patients with chronic heart failure imply that skeletal muscle blood flow must increase normally during muscle activation when only a small muscle mass is used. These results are not compatible with the concept of a generalised impairment of normal vasodilatation within active skeletal muscle. In contrast, activation of a large muscle, such as quadriceps, results in the rapid onset of fatigue in patients with severe chronic heart failure. This fatigue may be related to the inability of the cardiovascular system to provide the required blood flow for the activation of a large muscle mass. The finding of a relatively greater increase in fatigue of adductor pollicis during circulatory occlusion in patients with severe chronic heart failure supports the hypnosis of an intrinsic abnormality of skeletal muscle in these patients.

Background-C-type natriuretic peptide (CNP) is a vasodilator produced by the vascular endothelium. It shares structural and physiological properties with the cardiac hormones atrial natriuretic peptide and brain natriuretic peptide (BNP), but little is known about its pathophysiological role in chronic heart failure (CHF). We assessed the hypothesis that CNP is produced by the heart in patients with CHF. Methods and Results-Myocardial CNP production was determined (difference in plasma levels between the aortic root and coronary sinus [CS]) in 9 patients undergoing right and left heart catheterization as part of their CHF assessment (all male, age 59Ϯ9 years; New York Heart Association class 2.2Ϯ0.1; left ventricular ejection fraction 29Ϯ5%; creatinine 105Ϯ8 mol/L [all values meanϮSEM]). BNP, established as originating from myocardium, was assessed from the same samples as a positive control. Analyses were performed by a blinded operator using a standard competitive radioimmunoassay kit (Peninsula Laboratories, Bachem Ltd UK). A step-up (29%) in plasma CNP concentration was found from the aorta to the CS (3.55Ϯ1.53 versus 4.59Ϯ1.54 pg/mL, respectively; Pϭ0.035). The mean increase in CNP was 0.90Ϯ0.35 pg/mL (range 0.05 to 2.80 pg/mL). BNP levels increased by 57% from aorta to CS (86.0Ϯ20.5 versus 135.0Ϯ42.2 pg/mL; Pϭ0.01). CS CNP levels correlated with mean pulmonary capillary wedge pressure (rϭ0.82, Pϭ0.007). Conclusions-We have shown that CNP is produced by the heart in patients with CHF. Although further evaluation is required to define its full pathophysiological role in this condition, CNP may represent an important new local mediator in the heart. (Circulation. 2003;107:571-573.)